Diabetes, Vol 49, Issue 12 2039-2047, Copyright © 2000 by American Diabetes Association

ARTICLES

Hedgehog signaling regulation of insulin production by pancreatic beta-cells

MK Thomas, N Rastalsky, JH Lee and JF Habener
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston 02114, USA.

Hedgehogs (Hhs) are intercellular signaling molecules that regulate tissue patterning in mammalian development. Mammalian Hhs include Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh). The absence of Shh expression is required for the early development of the endocrine and exocrine pancreas, but whether Hh signaling functions in the fully developed adult endocrine pancreas is unknown. Here we report that Hhs Ihh and Dhh and their receptors patched (Ptc) and smoothened are expressed in the endocrine islets of Langerhans of the fully developed rat pancreas and in the clonal gamma-cell line INS-1. We demonstrate the coexpression of Ptc with insulin in beta-cells of mouse pancreatic islets, indicating that beta-cells are targets of active Hh signaling. The administration of cyclopamine, a Hh signaling inhibitor, decreases both insulin secretion from and insulin content of INS-1 cells. The effects of Hh signaling on insulin production occur at the transcriptional level because activation of Hh signal transduction by ectopic expression of Shh increases rat insulin I promoter activation in a dose-dependent manner in transient transfections of INS-1 and MIN6 beta-cell lines. In contrast, inhibition of Hh signaling with increasing concentrations of cyclopamine progressively reduces insulin promoter activity. Furthermore, the treatment of INS-1 cells with cyclopamine diminishes endogenous insulin mRNA expression. We propose that Hh signaling is not restricted to patterning in early pancreas development but also continues to signal in differentiated beta-cells of the endocrine pancreas in regulating insulin production. Thus, defective Hh signaling in the pancreas should be considered as a potential factor in the pathogenesis of type 2 diabetes.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. Ait-Lounis, D. Baas, E. Barras, C. Benadiba, A. Charollais, R. Nlend Nlend, D. Liegeois, P. Meda, B. Durand, and W. Reith Novel Function of the Ciliogenic Transcription Factor RFX3 in Development of the Endocrine Pancreas Diabetes, April 1, 2007; 56(4): 950 - 959. [Abstract] [Full Text] [PDF]

				M. C. Martinez, F. Larbret, F. Zobairi, J. Coulombe, N. Debili, W. Vainchenker, M. Ruat, and J.-M. Freyssinet Transfer of differentiation signal by membrane microvesicles harboring hedgehog morphogens Blood, November 1, 2006; 108(9): 3012 - 3020. [Abstract] [Full Text] [PDF]

				K. Eto, V. Kaur, and M. K. Thomas Regulation of Insulin Gene Transcription by the Immediate-Early Growth Response Gene Egr-1 Endocrinology, June 1, 2006; 147(6): 2923 - 2935. [Abstract] [Full Text] [PDF]

				J. L. Volinic, J. H. Lee, K. Eto, V. Kaur, and M. K. Thomas Overexpression of the Coactivator Bridge-1 Results in Insulin Deficiency and Diabetes Mol. Endocrinol., January 1, 2006; 20(1): 167 - 182. [Abstract] [Full Text] [PDF]

				D. Lu, T. Ventura-Holman, J. Li, R. W. McMurray, J. S. Subauste, and J. F. Maher Abnormal Glucose Homeostasis and Pancreatic Islet Function in Mice with Inactivation of the Fem1b Gene Mol. Cell. Biol., August 1, 2005; 25(15): 6570 - 6577. [Abstract] [Full Text] [PDF]

				J. Kaput, K. G. Klein, E. J. Reyes, W. A. Kibbe, C. A. Cooney, B. Jovanovic, W. J. Visek, and G. L. Wolff Identification of genes contributing to the obese yellow Avy phenotype: caloric restriction, genotype, diet x genotype interactions Physiol Genomics, August 11, 2004; 18(3): 316 - 324. [Abstract] [Full Text] [PDF]

				L. Wang, C. Coffinier, M. K. Thomas, L. Gresh, G. Eddu, T. Manor, L. L. Levitsky, M. Yaniv, and D. B. Rhoads Selective Deletion of the Hnf1{beta} (MODY5) Gene in {beta}-Cells Leads to Altered Gene Expression and Defective Insulin Release Endocrinology, August 1, 2004; 145(8): 3941 - 3949. [Abstract] [Full Text] [PDF]

				N. Ogawa, J. F. List, J. F. Habener, and T. Maki Cure of Overt Diabetes in NOD Mice by Transient Treatment With Anti-Lymphocyte Serum and Exendin-4 Diabetes, July 1, 2004; 53(7): 1700 - 1705. [Abstract] [Full Text] [PDF]

				V. Stanojevic, J. F. Habener, and M. K. Thomas Pancreas Duodenum Homeobox-1 Transcriptional Activation Requires Interactions with p300 Endocrinology, June 1, 2004; 145(6): 2918 - 2928. [Abstract] [Full Text] [PDF]

				H. Kawahira, N. H. Ma, E. S. Tzanakakis, A. P. McMahon, P.-T. Chuang, and M. Hebrok Combined activities of hedgehog signaling inhibitors regulate pancreas development Development, October 15, 2003; 130(20): 4871 - 4879. [Abstract] [Full Text] [PDF]

				R. Pola, L. E. Ling, T. R. Aprahamian, E. Barban, M. Bosch-Marce, C. Curry, M. Corbley, M. Kearney, J. M. Isner, and D. W. Losordo Postnatal Recapitulation of Embryonic Hedgehog Pathway in Response to Skeletal Muscle Ischemia Circulation, July 29, 2003; 108(4): 479 - 485. [Abstract] [Full Text] [PDF]

				H S Heussler and M Suri Sonic hedgehog Mol. Pathol., June 1, 2003; 56(3): 129 - 131. [Full Text] [PDF]

				J. A. Lowrey, G. A. Stewart, S. Lindey, G. F. Hoyne, M. J. Dallman, S. E. M. Howie, and J. R. Lamb Sonic Hedgehog Promotes Cell Cycle Progression in Activated Peripheral CD4+ T Lymphocytes J. Immunol., August 15, 2002; 169(4): 1869 - 1875. [Abstract] [Full Text] [PDF]

				M. K. Thomas, J. H. Lee, N. Rastalsky, and J. F. Habener Hedgehog Signaling Regulation of Homeodomain Protein Islet Duodenum Homeobox-1 Expression in Pancreatic {{beta}}-Cells Endocrinology, March 1, 2001; 142(3): 1033 - 1040. [Abstract] [Full Text] [PDF]